1.1 Hemophilia A

HUMATE-P, Antihemophilic Factor/von Willebrand Factor Complex (Human), is indicated for treatment and prevention of bleeding in adults with hemophilia A (classical hemophilia).

1.2 Von Willebrand Disease (VWD)

HUMATE-P is also indicated in adult and pediatric patients with von Willebrand disease (VWD) for:

(1)

treatment of spontaneous and trauma-induced bleeding episodes, and

(2)

prevention of excessive bleeding during and after surgery. This applies to patients with severe VWD as well as patients with mild to moderate VWD where use of desmopressin (DDAVP) is known or suspected to be inadequate.

Controlled clinical trials to evaluate the safety and efficacy of prophylactic dosing with HUMATE-P to prevent spontaneous bleeding have not been conducted in VWD subjects [see Clinical Studies (14)].

2.1 Therapy for Hemophilia A

One International Unit (IU) of Factor VIII (FVIII) activity per kg body weight will increase the circulating FVIII level by approximately 2.0 International Units (IU)/dL. Dosage must be individualized based on the patient's weight, type and severity of hemorrhage, FVIII level, and presence of inhibitors. Judge the adequacy of treatment by clinical effects and, in all cases, adjust doses as needed based on clinical judgment and on frequent monitoring of the patient's FVIII level. Table 1 provides dosing recommendations for the treatment of hemophilia A in adults.

2.2 Treatment of Bleeding Episodes in VWD

Administer 40 to 80 International Units (IU) VWF:RCo (corresponding to 17 to 33 International Units (IU) FVIII in HUMATE-P) per kg body weight every 8 to 12 hours. Adjust the dosage based on the extent and location of bleeding. Administer repeat doses as long as needed based on monitoring of appropriate clinical and laboratory measures [see Warnings and Precautions (5.2, 5.3)]. Expected levels of VWF:RCo are based on an expected in vivo recovery (IVR) of 2.0 International Units (IU)/dL rise per International Unit (IU)/kg VWF:RCo administered. The administration of 1 International Unit (IU) of FVIII per kg body weight can be expected to lead to a rise in circulating VWF:RCo of approximately 5 International Units (IU)/dL. Table 2 provides dosing recommendations for adult and pediatric patients [see Use in Specific Populations (8.4)].2

2.3 Prevention of Excessive Bleeding During and After Surgery in VWD

The following information provides guidelines for calculating loading and maintenance doses of HUMATE-P for patients undergoing surgery. However in the case of emergency surgery, administer a loading dose of 50 to 60 International Units (IU) VWF:RCo/kg body weight and, subsequently, closely monitor the patient's trough coagulation factor levels.

Measure incremental IVR and assess plasma VWF:RCo and FVIII:C levels in all patients prior to surgery when possible.

To determine IVR:

1. Measure the baseline plasma VWF:RCo level.
2. Infuse a calculated dose [International Units (IU)/kg] of VWF:RCo product intravenously at "time 0".
3. At "time+30 minutes", measure the plasma VWF:RCo level.

Use the following formula to calculate IVR:

IVR = (Plasma VWF:RCotime+30 min – Plasma VWF:RCobaseline International Units (IU)/dL)
Calculated dose (International Units (IU)/kg)

For example, assuming a baseline VWF:RCo of 30 International Units (IU)/dL at "time 0", a calculated dose of 60 International Units (IU)/kg, and a VWF:RCo of 120 International Units (IU)/dL at "time+30 minutes", the IVR would be 1.5 International Units (IU)/dL per International Units (IU)/kg of VWF:RCo administered.

2.4 Reconstitution

• Prepare and administer using aseptic techniques.
• Use either the Mix2Vial® filter transfer set provided with HUMATE-P [see How Supplied/Storage and Handling (16)] or a commercially available double-ended needle and vented filter spike.
• Use plastic disposable syringes with HUMATE-P. Protein solutions of this type tend to adhere to the ground glass surface of all-glass syringes.
• Reconstitute HUMATE-P at room temperature as follows:

1. Ensure that the HUMATE-P vial and diluent vial are at room temperature.
2. Place the HUMATE-P vial, diluent vial and Mix2Vial transfer set on a flat surface.
3. Remove the HUMATE-P and diluent vial flip caps. Wipe the stoppers with an alcohol swab and allow the stoppers to dry prior to opening the Mix2Vial transfer set package.
4. Open the Mix2Vial transfer set package by peeling away the lid (Fig. 1). Leave the Mix2Vial transfer set in the clear package.

   Fig. 1

5. Place the diluent vial on a flat surface and hold the vial tightly. Grip the Mix2Vial transfer set together with the clear package and push the plastic spike at the blue end of the Mix2Vial transfer set firmly through the center of the stopper of the diluent vial (Fig. 2).

   Fig. 2

6. Carefully remove the clear package from the Mix2Vial transfer set. Make sure that you pull up only the clear package, not the Mix2Vial transfer set (Fig. 3).

   Fig. 3

7. With the HUMATE-P vial placed firmly on a flat surface, invert the diluent vial with the Mix2Vial transfer set attached and push the plastic spike of the transparent adapter firmly through the center of the stopper of the HUMATE-P vial (Fig. 4). The diluent will automatically transfer into the HUMATE-P vial.

   Fig. 4

8. With the diluent and Humate-P vial still attached to the Mix2Vial transfer set, gently swirl the HUMATE-P vial to ensure that the HUMATE-P is fully dissolved (Fig. 5). Do not shake the vial.

   Fig. 5

9. With one hand grasp the HUMATE-P side of the Mix2Vial transfer set and with the other hand grasp the blue diluent-side of the Mix2Vial transfer set, and unscrew the set into two pieces (Fig. 6).

   Fig. 6

10. Draw air into an empty, sterile syringe. While the HUMATE-P vial is upright, screw the syringe to the Mix2Vial transfer set. Inject air into the HUMATE-P vial. While keeping the syringe plunger pressed, invert the system upside down and draw the concentrate into the syringe by pulling the plunger back slowly (Fig. 7).

    Fig. 7

11. Now that the concentrate has been transferred into the syringe, firmly grasp the barrel of the syringe (keeping the syringe plunger facing down) and unscrew the syringe from the Mix2Vial transfer set (Fig. 8). Attach the syringe to a suitable intravenous administration set.

    Fig. 8

12. If patient requires more than one vial, pool the contents of multiple vials into one syringe. Use a separate unused Mix2Vial for each product vial.

2.5 Administration

HUMATE-P is for intravenous use only.

• The solution should be clear or slightly opalescent. After filtering/withdrawal, the reconstituted product should be inspected visually for particulate matter and discoloration prior to administration. Even if the directions for use for the reconstitution procedure are precisely followed, it is not uncommon for a few flakes or particles to remain. The filter included in the Mix2Vial device removes those particles completely. Filtration does not influence dosage calculations. Do not use visibly cloudy solutions or solutions still containing flakes or particles after filtration.
• Do not refrigerate HUMATE-P after reconstitution. Administer within 3 hours after reconstitution.
• Slowly infuse the solution (maximally 4 mL/minute) with a suitable intravenous administration set.
• Discard the administration equipment and any unused HUMATE-P after use.

5.1 Thromboembolic Events (VWD Patients)

Thromboembolic events have been reported in VWD patients receiving Antihemophilic Factor/von Willebrand Factor Complex replacement therapy, especially in the setting of known risk factors for thrombosis.3,4 Early reports indicate a higher incidence may occur in females. Endogenous high levels of FVIII have also been associated with thrombosis, but no causal relationship has been established. Exercise caution and consider antithrombotic measures in all at-risk VWD patients who are receiving coagulation factor replacement therapy.

5.2 Monitoring for Intravascular Hemolysis

HUMATE-P contains blood group isoagglutinins (anti-A and anti-B). When doses are very large or need to be repeated frequently (for example, when inhibitors are present or when pre- and post-surgical care is involved), monitor patients of blood groups A, B, and AB for signs of intravascular hemolysis and decreasing hematocrit values and treat appropriately.

5.3 Monitoring VWF:RCo and FVIII Levels

Monitor the VWF:RCo and FVIII levels of VWD patients receiving HUMATE-P using standard coagulation tests, especially in cases of surgery. It is advisable to monitor trough VWF:RCo and FVIII:C levels at least once a day in order to adjust the dosage of HUMATE-P as needed to avoid excessive accumulation of coagulation factors [see Dosage and Administration (2.2, 2.3)].

5.4 Transmission of Infectious Agents

Because HUMATE-P is made from human blood, it may carry a risk of transmitting infectious agents, e.g., viruses, the variant Creutzfeldt-Jakob disease (vCJD) agent and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent [see Description (11) and Patient Counseling Information (17)]. The risk that such products will transmit an infectious agent has been reduced by screening plasma donors for prior exposure to certain viruses, by testing for the presence of certain current virus infections, and by inactivating and/or removing certain viruses during manufacturing [see Description (11)].

Despite these measures, such products can still potentially transmit disease. There is also the possibility that unknown infectious agents may be present in such products. Thus the risk of transmission of infectious agents cannot be eliminated completely. Report all infections thought by a physician possibly to have been transmitted by this product to CSL Behring Pharmacovigilance at 1-866-915-6958 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Some viruses, such as Parvovirus B19 virus (B19V) or hepatitis A (HAV), are particularly difficult to remove or inactivate. B19V may most seriously affect pregnant women and immune-compromised individuals.

Although the overwhelming number of B19V and HAV cases are community acquired, reports of these infections have been associated with the use of some plasma-derived products. Therefore, physicians should be alert to the potential symptoms of B19V and HAV infections [see Patient Counseling Information (17)].

Symptoms of B19V may include low-grade fever, rash, arthralgia, and transient symmetric, nondestructive arthritis. Diagnosis is often established by measuring B19V-specific IgM and IgG antibodies. Symptoms of HAV include low-grade fever, anorexia, nausea, vomiting, fatigue, and jaundice. A diagnosis may be established by measuring specific IgM antibodies.

Physicians should strongly consider administration of hepatitis A and hepatitis B vaccines to individuals receiving plasma derivatives. Potential risks and benefits of vaccination should be weighed by the physician and discussed with the patient.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in practice.

6.2 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of HUMATE-P. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to HUMATE-P exposure.

Adverse reactions reported in patients receiving HUMATE-P for treatment of VWD or hemophilia A are allergic-anaphylactic reactions (including urticaria, chest tightness, rash, pruritus, edema, and shock), development of inhibitors to FVIII, and hemolysis. Additional adverse reactions reported for VWD are thromboembolic complications, chills and fever, and hypervolemia.

8.1 Pregnancy

Animal reproduction studies have not been conducted with HUMATE-P. It is also not known whether HUMATE-P can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. HUMATE-P should be given to a pregnant woman only if clearly needed.

8.2 Labor and Delivery

It is not known whether HUMATE-P can cause harm to the mother or the fetus when administered during labor and delivery. HUMATE-P should be given during labor and delivery only if clearly needed.

8.3 Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when HUMATE-P is administered to a nursing woman.

8.4 Pediatric Use

8.5 Geriatric Use

Clinical studies of HUMATE-P did not include sufficient numbers of subjects 65 years of age and older to determine whether they respond differently from younger subjects. As for all patients, dosing for geriatric patients should be appropriate to their overall situation.

12.1 Mechanism of Action

The active components of HUMATE-P consist of two different noncovalently bound proteins (FVIII and VWF). FVIII is an essential cofactor in activation of factor X, leading ultimately to the formation of thrombin and, subsequently, fibrin. VWF promotes platelet aggregation and platelet adhesion on damaged vascular endothelium; activated platelets interact with clotting proteins to form a clot. VWF also serves as a stabilizing carrier protein for the procoagulant protein FVIII.5,6 The activity of VWF is measured as VWF:RCo.

12.3 Pharmacokinetics

14.1 Treatment of Bleeding Episodes in VWD

Clinical efficacy of HUMATE-P in the control of bleeding in subjects with VWD was determined by a retrospective review of clinical safety and efficacy data obtained from 97 Canadian VWD subjects who received product under an Emergency Drug Release Program. The dosage schedule and duration of therapy were determined by the medical practitioner.

There were 514 requests for product use for surgery, bleeding, or prophylaxis in the 97 subjects. Of these, HUMATE-P was not used in 151 cases, and follow-up safety and/or efficacy information was available for 303 (83%) of the remaining 363 requests. In many cases, HUMATE-P from a single request was used for several treatment courses in one subject. Therefore, there are more reported treatment courses than requests.

HUMATE-P was administered to 97 subjects in 530 treatment courses: 73 for surgery, 344 for treatment of bleeding, and 20 for prophylaxis of bleeding. The majority of the 93 "other" uses involved dental procedures, diagnostic procedures, prophylaxis prior to a procedure, or test doses.

Table 10 summarizes the dosing information (all subjects) for bleeding episodes.

14.2 Prevention of Excessive Bleeding During and After Surgery in VWD

Two prospective, open-label, non-controlled, multicenter clinical studies, one in the US and one in Europe, investigated the safety and hemostatic efficacy of HUMATE-P in subjects with VWD undergoing surgery.

14.3 Virus Transmission Studies

Clinical evidence of the absence of virus transmission in HUMATE-P was obtained in additional studies.

In one study, none of the evaluable subjects (31 of 67) who received HUMATE-P developed HBV infection or showed clinical signs of non-A, non-B (NANB) hepatitis infection.

In another study, 32 lots of HUMATE-P were administered to 26 subjects with hemophilia or VWD who had not previously received any blood products. No subject developed any signs of an infectious disease, and the 10 subjects not previously vaccinated remained seronegative for markers of infection with HBV, HAV, cytomegalovirus (CMV), Epstein-Barr virus, and HIV.

In a retrospective study, 155 subjects evaluated remained negative for the presence of HIV-1 antibodies for time periods ranging from 4 months to 9 years from the initial administration of HUMATE-P. All 67 of the subjects tested for HIV-2 antibodies remained seronegative.

Table 14. How Supplied

Each product presentation includes a package insert and the following components: